Metabolic-associated fatty liver disease (MAFLD) has become an increasingly prevalent liver disorder worldwide, being closely associated with obesity, metabolic syndrome, and insulin resistance. Bile acids (BAs), beyond their traditional role in lipid digestion, play a pivotal part in regulating lipid and glucose metabolism as well as inflammatory responses. Recent investigations have recognized BAs as key factors in the onset and progression of MAFLD, mainly via their interactions with nuclear receptors such as the farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor (TGR5). Additionally, active compounds derived from traditional Chinese medicine (TCM) have shown promising potential in the treatment of MAFLD. This study systematically reviews and analyzes the molecular mechanisms and recent progress in the application of TCM active ingredients for MAFLD treatment, with a focus on their regulation of BAs. These active ingredients, including saponins, flavonoids, polysaccharides, and sterols, exert therapeutic effects through diverse mechanisms, such as modulating BA synthesis and mediating receptor-signaling pathways, and are expected to restore metabolic homeostasis.

Temporal lobe epilepsy (TLE) arises mostly because of an initial injury. Certain stimuli can make a normal brain prone to repeated, spontaneous seizures via a process called epileptogenesis. This study examined the plasma metabolomics profile in rats with the induced TLE to identify feasible biomarkers that can distinguish progression of epileptogenesis in three different time points and reveal the underlying mechanisms of epileptogenesis. Status epilepticus (SE) was induced by repetitive intraperitoneal injections of low-dose lithium chloride-pilocarpine hydrocholoride. Blood samples were collected 48 h, 1 week, and 6 weeks after SE, respectively. Plasma metabolites were analyzed by nuclear magnetic resonance (NMR) spectrometry. Statistical analysis was performed using MetaboAnalyst 6.0. An orthogonal partial least squares discriminant analysis (OPLS-DA) model was employed to represent variations between the TLE model groups and respective controls. Volcano plot analysis was used to identify key features, applying a fold-change criterion of 1.5 and a t-test threshold of 0.05. 48 h after SE, dimethyl sulfone (DMSO2) and creatinine levels were decreased, whereas glycine and creatine levels were increased. The only metabolite that changed 1 week after SE was pyruvic acid, which was increased compared to its control level. Lactic acid, pyruvic acid, and succinic acid levels were increased 6 weeks after SE. The identified metabolites were especially related to the tricarboxylic acid cycle and glycine, serine, and threonine metabolism. The results illustrate that distinct plasma metabolites can function as phase-specific biomarkers in TLE and reveal new insights into the mechanisms underlying SE.

The purpose of this research was to investigate how different bile acids impact lipid metabolism and carcass characteristics in finishing pigs, along with the potential mechanisms involved. Twenty-one finishing pigs (Duroc×Landrace×Yorkshire [DLY]; average BW = 144.38 ± 8.92 kg) were assigned to three dietary treatments, with each treatment containing seven replicates, each consisting of one pig. The three dietary treatments included: a basic diet, a basic diet supplemented with 500 mg/kg of hyodeoxycholic acid (HDCA), and a basic diet supplemented with 500 mg/kg of lithocholic acid (LCA). The trial lasted for 28 d. Hyodeoxycholic acid was used in the in vitro experiments and added to mature 3T3-L1 adipocytes for 4 d to elucidate the mechanism by which bile acids regulate lipid metabolism. The results suggested that HDCA tended to decrease backfat thickness in finishing pigs (P = 0.094) and reduced the size of lipid droplets in 3T3-L1 adipocytes (P = 0.012), whereas LCA increased backfat thickness (P = 0.016) and induced larger lipid droplets in the abdominal adipose tissue (P = 0.003). Furthermore, HDCA enhanced the expression of Takeda G-protein-coupled receptor 5 protein and hormone-sensitive lipase (HSL) gene in backfat of pigs (P < 0.05) and increased the protein expression of phosphorylated HSL (p-HSL) in vitro (P = 0.093). Compared to HDCA, LCA addition increased the gene and protein expression of peroxisome proliferator activated receptor gamma in backfat of pigs (P < 0.05) and enhanced the expression of hepatic genes sterol regulatory element-binding protein-1c and fatty acid synthase (P < 0.05). In conclusion, HDCA enhanced lipolysis and partially decreased backfat thickness in finishing pigs, while LCA promoted lipid synthesis and increased backfat thickness of pigs. The variations in the effects of various bile acids on bile acid receptors could explain these functional differences.

Bile salt hydrolase (BSH) is produced by gut bacteria and is responsible for deconjugating amino acids from the aliphatic side chains of conjugated bile acids (BAs), initiating the critical first step in BAs metabolism. Lead (Pb) is known to cause gut microbial dysbiosis, but whether it affects BAs profiles by reshaping the gut microbiota remains elusive. Here, using targeted BAs metabolomics and metagenomics sequencing, we found that 200 μg/L Pb treatment led to a significant increase in the abundance of BSH-producing microbiota (e.g., Eubacterium and Yersinia), thus promoting the deconjugation of taurocholic acid (TCA) and taurochenodeoxycholic acid (TCDCA). Consequently, the accumulation of relatively hydrophobic BAs cholic acid (CA) and chenodeoxycholic acid (CDCA) may cause damage to enterocytes (e.g., reduced microvilli and enterocyte heights), which attenuated tadpole digestion and ultimately led to significant reductions in morphological parameters. The inhibition of tadpole growth by Pb toxicity may negatively affect their survival and even increase their risk of death. Overall, these results revealed for the first time the toxicological mechanism by which Pb reshapes the gut microbiota and thus disrupts the BAs profile, shedding new insights into the detrimental effects of Pb toxicity on amphibian growth.

Most forms of obesity are associated with chronic diseases that remain a global public health challenge.

Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation.

This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long-term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity-related cardiometabolic risks. Moreover, the socio-economic drivers of obesity and its transition across phenotypes remain poorly understood.

The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community-level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies.

The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity.

This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio-economic model not compatible with optimal human health.

Bile salts are steroids with distinctive hydroxylation patterns that are produced and excreted by vertebrates. In contrast to common human bile salts, ursodeoxycholate (UDCA) has a 7-hydroxy group in β-configuration and is used in large amounts for the treatment of diverse gastrointestinal diseases. We isolated the 7β-hydroxysteroid dehydratase Hsh3 that is involved in UDCA degradation by Sphingobium sp. strain Chol11. Hsh3 eliminates the 7β-hydroxy group as water, leading to a double bond in the B-ring. This is similar to 7α-hydroxysteroid dehydratases in this and other strains, but Hsh3 is evolutionarily different from these. Purified Hsh3 accepted steroids with and without side chains as substrates and had minor activity with 7α-hydroxy groups. The deletion mutant strain Chol11 Δhsh3 had impacted growth with UDCA and accumulated a novel compound. The compound was identified as 3',5-dihydroxy-H-methyl-hexahydro-5-indene-1-one-propanoate, consisting of steroid rings C and D with a C3-side chain carrying the former 7β-hydroxy group, indicating that Hsh3 activity is important especially for the later stages of bile salt degradation. Hsh3 homologs were found in other sphingomonads that were also able to degrade UDCA as well as in environmental metagenomes. Thus, Hsh3 adds to the bacterial enzyme repertoire for degrading a variety of differently hydroxylated bile salts.IMPORTANCEThe bacterial degradation of different bile salts is not only important for the removal of these steroidal compounds from the environment but also harbors interesting enzymes for steroid biotechnology. The 7β-hydroxy bile salt ursodeoxycholate (UDCA) naturally occurs in high concentration in the feces of black bears and has important pharmaceutical relevance for the treatment of different liver-related diseases, for which it is administered in high and increasing amounts. Additionally, it is present in the bile salt pool of humans in trace amounts. While UDCA degradation is environmentally important, the enzyme Hsh3 modifies the hydroxy group that confers the medically relevant properties and thus might be interesting for microbiome analyses and biotechnological applications.

Bile acid metabolism and antitumor immunity are both disrupted during liver cancer progression. However, the complex regulatory relationship between them remains largely unclear. Here, we find that loss of aldo-keto reductase 1D1 (AKR1D1) promotes the accumulation of isolithocholic acid (iso-LCA) through gut microbiome dysregulation, thereby impairing the cytotoxic function of natural killer (NK) cells and leading to the accelerated development of hepatocellular carcinoma (HCC). Mechanistically, AKR1D1 deficiency leads to an increased proportion of Bacteroidetes ovatus (B. ovatus), which breaks down chenodeoxycholic acid (CDCA) into iso-LCA. Moreover, accumulated iso-LCA impairs the antitumor activity of hepatic NK cells in a phosphorylated-CREB1 (p-CREB1)-dependent manner. The potassium-sparing diuretic spironolactone treatment significantly enhances the inhibitory effect of anti-PD1 antibody on HCC progression by targeting iso-LCA-mediated tumor immune escape. Taken together, our results uncover a previously unappreciated link between AKR1D1 and HCC and suggest that targeting iso-LCA produced by B. ovatus might be a promising strategy to activate NK cell cytotoxicity to treat HCC.

High plasma bile acid (BA) levels in individuals with cholestasis affect adenosine (Ado) receptor (AdoR) signaling, but the underlying mechanisms are unclear. Here, we investigated BA interference with cellular Ado transport as a putative mechanism for altering extracellular Ado availability for AdoR signaling. Computational modeling and experimental studies revealed that equilibrative nucleoside transporter 2 (ENT2), but not ENT1, is capable of translocating BAs across the mammalian plasma membrane. ENT2-mediated BA transport has low affinity, is pH independent, and is partially sensitive to inhibition by nitrobenzylthioinosine (NBMPR). At cholestatic plasma concentrations of BAs, however, BAs interfere with Na+-independent, NBMPR-sensitive, ENTs without affecting Na+-driven, NBMPR-insensitive, concentrative nucleoside transporters (CNTs). Interestingly, this BA interference with ENT transport was largely selective for Ado, with minimal to no impact on the transport of other purine or pyrimidine nucleosides. Xenopus oocyte-based studies demonstrated that BA inhibition of Ado transport is in the order ENT3≥ENT2>ENT1, which also corresponds to the intrinsic ability of individual ENTs to transport BAs. In silico analysis revealed that Ado and BA tend to occupy similar spaces within the ENT translocation pores and that the polar and hydrophilic pore-lining residues determine the interaction of ENTs with BAs. Furthermore, in vivo studies indicated that the accumulation of extraneously administered Ado decreases in the livers of cholestatic mice and that interference with Ado transport alters AdoR signaling. Together, these findings reveal novel ENT-dependent BA‒Ado interactions that may have implications for BA dysregulation of AdoR signaling in cholestatic liver diseases.

Bile acids and their corresponding intestinal epithelial receptors, the farnesoid X receptor (FXR), the G protein-coupled bile acid receptor (TGR5), play crucial roles in the physiological and pathological processes of intestinal epithelial cells. These acids and receptors are involved in the regulation of intestinal absorption, signal transduction, cellular proliferation and repair, cellular senescence, energy metabolism, and the modulation of gut microbiota. A comprehensive literature search was conducted using PubMed, employing keywords such as bile acid, bile acid receptor, FXR (nr1h4), TGR5 (gpbar1), intestinal epithelial cells, proliferation, differentiation, senescence, energy metabolism, gut microbiota, inflammatory bowel disease (IBD), colorectal cancer (CRC), and irritable bowel syndrome (IBS), with a focus on publications available in English. This review examines the diverse effects of bile acid signaling and bile receptor pathways on the proliferation, differentiation, senescence, and energy metabolism of intestinal epithelial cells. Additionally, it explores the interactions between bile acids, their receptors, and the microbiota, as well as the implications of these interactions for host health, particularly in relation to prevalent intestinal diseases. Finally, the review highlights the importance of developing highly specific ligands for FXR and TGR5 receptors in the context of metabolic and intestinal disorders.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex metabolic disorder characterized by hepatic lipid accumulation and subsequent inflammation. This condition is closely linked to metabolic syndrome and obesity, with its prevalence rising due to sedentary lifestyles and high-calorie diets. The pathogenesis of MAFLD involves multiple factors, including insulin resistance, lipotoxicity, oxidative stress, and inflammatory responses. The gut microbiota plays a crucial role in MAFLD development, with dysbiosis contributing to liver inflammation through various mechanisms, such as enhanced intestinal permeability and the translocation of bacterial products like lipopolysaccharide (LPS). Microbial metabolites, including short-chain fatty acids (SCFAs) and bile acids, influence hepatic function and immune responses, with potential implications for disease progression. Specific gut microbiome signatures have been identified in MAFLD patients, offering potential diagnostic and therapeutic targets. Moreover, gut-derived toxins, such as endotoxins, lipopolysaccharides, trimethylamine-N-oxide and bacterial metabolites, significantly influence liver damage and inflammation, highlighting the complex interplay between the gut microbiome and hepatic health. This review comprehensively examines the complex interplay between the gut microbiota and MAFLD, focusing on underlying pathogenic mechanisms, potential biomarkers, and emerging microbiome-targeted therapeutic strategies for disease management.

The invasive nature of sample collection for studying the small intestinal (SI) microbiome often results in its poor characterization. This study evaluated a novel ingestible medical device (MD) for SI luminal sample collection. A monocentric interventional trial (NCT05477069) was conducted on 15 healthy subjects. Metagenomics, metabolomics and culturomics assessed the MD's effectiveness in characterizing the healthy SI microbiome and identifying potential biomarkers. The SI microbiota differed significantly from the fecal microbiota, displaying high inter-individual variability, lower species richness, and reduced alpha diversity. A combined untargeted and semi-targeted LC-MS/MS metabolomics approach identified a distinct SI metabolic footprint, with bile acids and amino acids being the most abundant classes of metabolites. Host and host/microbe-derived bile acids were particularly abundant in SI samples. The application of a fast culturomics approach to two SI samples enabled species-level characterization, resulting in the identification of 90 bacterial species, including five potential novel species. The present study demonstrates the efficacy of our novel sampling MD in enabling comprehensive SI microbiome analysis through an integrative multi-omics approach, allowing the identification of distinct microbiome signatures between SI and fecal samples.

Psoraleae Fructus (PF), the dried mature fruit of the leguminous plant Psoralea corylifolia L., is often used as a nutraceutical and to treat ulcerative colitis (UC). However, recently there have been reports of PF-induced liver injury.

To investigate the difference and mechanism of hepatotoxicity between normal and UC rats oral administration with PF, and clarify the relationship between PF risk and disease status.

PF water extracts (at the human equivalent dosage and 8-fold greater; 0.7 and 5.6 g/kg/day, respectively) were given to normal and UC rats for 4 weeks, and the general behaviors and colonic mucosal conditions were observed. The liver injury and its mechanism were studied by blood biochemistry, coagulation time, liver hematoxylin and eosin (H&E) staining, bile acids (BAs) metabolism, transcriptome analysis, quantitative real-time polymerase chain reaction (qRT‒PCR) and western blot (WB)experiments.

Normal rats receiving 5.6 g/kg PF water extract showed significantly increased serum levels of total bilirubin (TBIL) and total bile acids (TBA), significantly prolonged activated partial thromboplastin time (APTT), prothrombin time (PT) and thromboplastin time (TT), and slightly swollen hepatocytes, and obvious hepatobiliary hyperplasia. These liver injuries may be related to disordered BAs metabolism: the levels of farnesoid x receptor (FXR) and sulfotransferase family 2A member 1/2 (SULT2a1/a2) were down-regulated, whereas the levels of microsomal epoxide hydrolase (mEH), organic anion transporting polypeptide (OATP) and multidrug resistance-associated protein 3 (MRP3) were up-regulated, leading to liver and blood UnconBA and GlycineBA accumulation. However, at the same dose, UC model rats exhibited no obvious liver damage.

Normal rats, but not UC rats, displayed signs of liver injury in response to 5.6 g/kg PF water extract administration. Therefore, we recommend that healthy individuals should be aware of the potential risks associated with PF, and other patients should take PF according to their physician's guidance.

This study investigated the effects of ursodeoxycholic acid (UDCA) and bile salt (BAS) supplementation on lactation performance, health, and gut microbiota in periparturient dairy cows. Fifty-one Holstein dairy cows were selected at d -28 before parturition and blocked into 3 dietary treatments, including the control (CON; n = 17) received a basal diet, whereas the UDCA (n = 17) and BAS groups (n = 17) were supplemented with 10 g/d UDCA and 20 g/d BAS from d -21 to +21, with an observation phase until d +35. Milk yield and composition were recorded weekly, whereas the DMI were measured biweekly. Blood samples were collected at d +7 and +21, whereas rumen fluid and fecal samples were collected at d +21. Milk yield was significantly higher in the UDCA group at d +21 compared with the CON group, whereas on d +28, milk yield was significantly higher in both the UDCA and BAS groups compared with the CON group, and the DMI of the UDCA group showed an increased tendency at prepartum. Plasma nonesterified fatty acids were significantly higher in the BAS group, whereas Ala aminotransferase content were significantly lower in the UDCA group compared with the control. Furthermore, the cholesterol, malondialdehyde, oxidative stress index, serum amyloid A, and haptoglobin content were significantly lower in the UDCA and BAS groups. In total, 35, 43, and 45 plasma bile acids (BA) were detected in the control, UDCA, and BAS groups, respectively. Compared with the control, 8 key BA, including UDCA, tauroursodeoxycholic acid, glycoursodeoxycholic acid, and 5 key BA, including tauro-β-muricholic acid and hyocholic acid, were identified in the UDCA and BAS groups, respectively. The concentrations of total VFA and acetate in the UDCA and BAS groups was higher than that in the CON group, and the concentration of propionate tended to be higher. The β-diversity of both rumen and gut microbiota was significantly higher in the CON, UDCA, and BAS groups, whereas no significant changes were observed in α-diversity. Key rumen VFA-production bacteria, including Prevotella_7, Succinivibrionaceae_UCG-001, and Selenomonas, were enriched in the UDCA and BAS groups, along with an increase in beneficial gut microbiota, such as Butyrivibrio, Ruminococcus, and Caproiciproducen, and a reduction in harmful bacteria, such as Stenotrophomonas and Chryseobacterium. These findings suggest that the observed improvements in production performance and health may be mediated by alterations in peripheral BA and rumen and gut microbiota, offering insights for optimizing the nutrition and health of transitional dairy cows.

Deoxynivalenol (DON) is a widespread mycotoxin which contaminates several crops, including maize, wheat, and barley. In this study, we investigated the effects of orally administered DON on growth performance, blood biochemistry, histology, the gut microbiome, and metabolism in rats. Six-week-old rats, acclimatized for one week, were subjected to different dietary treatments for 42 days, as follows: CON (control): 0.9% saline; T1: 0.5 ppm DON; T2: 50 ppm DON; and T3: 100 ppm DON. The T3 group had the lowest final body weight (298.5 ± 3.69 g) and average daily gain compared with the control group (338.9 ± 6.43 g, p < 0.05). The feed conversion ratio was highest in the T3 group (4.28 ± 0.28) compared with that in the control group (3.12 ± 0.13, p < 0.05). DON treatment significantly reduced serum levels of creatinine, amylase, urea nitrogen, and alkaline phosphatase, but not alanine aminotransferase. Fibrosis and apoptosis were exacerbated in various tissues with increasing DON concentration. The metabolite profiles of several tissues were significantly different in the DON-treated and control groups. In the cecum, DON treatment increased the abundance of Desulfobacteria, while decreasing that of Firmicutes. Our results indicate that DON levels above the maximum residue limit have serious health consequences for animals.

Prenatal dexamethasone exposure (PDE) can impact adrenal corticosteroid synthesis in adult offspring. Furthermore, the adrenal gland can autonomously synthesize bile acids, but local bile acids accumulation has cytotoxic effects. This study found that PDE increased histone 3 lysine 27 acetylation (H3K27ac) levels in the promoter region of cholesterol 27 hydroxylase (CYP27A1) and its expression, as well as total bile acids (TBA) concentrations and enhanced endoplasmic reticulum stress (ERS) and inhibit steroid synthesis in adult male offspring rat adrenal glands. However, it is reversed in females. Tracing back to the prenatal stage and in combination with cellular experiments, it is further revealed that dexamethasone can regulate glucocorticoid receptor (GR)/SET binding protein 1 (SETBP1)/CYP27A1 signal pathway, consequently cause intracellular increase of bile acids. Finally, administration of nilvadipine (CYP27A1 inhibitor) to male offspring for 4 weeks after birth resulted in the reversal of PDE-induced adrenal morphological and functional damage. In conclusion, PDE induces fetal adrenal corticosteroid dysfunction in adult male offspring by upregulating CYP27A1 promoter region H3K27ac levels and expression in the adrenal gland through the GR/SETBP1 signaling pathway. This effect persists beyond birth, leading to bile acids local increase and subsequent enhancement of ERS, ultimately inducing cellular dysfunction in adult adrenal glands.

In the current era, metabolic dysfunction-associated steatotic liver disease (MASLD) has gradually developed into a major type of chronic liver disease that is widespread globally. Numerous studies have shown that the gut microbiota plays a crucial and indispensable role in the progression of MASLD. Currently, the gut microbiota has become one of the important entry points for the research of this disease. Therefore, the aim of this review is to elaborate on the further associations between the gut microbiota and MASLD, including the changes and differences in the microbiota between the healthy liver and the diseased liver. Meanwhile, considering that metabolic dysfunction-associated fatty liver and metabolic dysfunction-associated steatohepatitis are abnormal pathological states in the development of the disease and that the liver exhibits different degrees of fibrosis (such as mild fibrosis and severe fibrosis) during the disease progression, we also conduct a comparison of the microbiota in these states and use them as markers of disease progression. It reveals the changes in the production and action mechanisms of short-chain fatty acids and bile acids brought about by changes in the gut microbiota, and the impact of lipopolysaccharide from Gram-negative bacteria on the disease. In addition, the regulation of the gut microbiota in disease and the production and inhibition of related disease factors by the use of probiotics (including new-generation probiotics) will be explored, which will help to monitor the disease progression of patients with different gut microbiota compositions in the future and carry out personalized targeted therapies for the gut microbiota. This will achieve important progress in preventing and combating this disease.

Serum total bile acid (TBA) levels are frequently assessed in clinical routine for the early detection of hepatobiliary dysfunction. However, the comparability of current 5th-generation TBA cycle assays based on 3α-hydroxysteroid dehydrogenase (3α-HSD) and their ability to quantify individual bile acids has not been systematically addressed.

Patient serum samples (n=60) across the diagnostically relevant TBA range (1-200 μmol/L) were analyzed using five TBA routine assays from Abbott, DiaSys, Diazyme, Beijing Strong (BSBE) and Randox on the same analyzer (BioMajesty® JCA-BM6010/C). The assays were compared using Passing-Bablok regression and the recovery of 11 individual BAs was evaluated against RP-HPLC-MS/MS as non-enzymatic reference method.

Despite excellent correlation (Spearman r ≥0.99), the assays showed proportional differences (slope) ranging from 0.99 (BSBE/Randox) to 1.24 (Abbott/DiaSys). The assays showed considerable deviation in the recovery of competitor's calibrators and controls, and large heterogeneity in the recovery of individual BAs, with mean deviations from reference value between 13 % (DiaSys) and 42 % (Abbott). CA and TCA were measured most accurately and consistently, whereas GCA, CDCA, DCA, UDCA, and conjugates were over- or undermeasured to varying degrees.

The linear relationship and constant proportional bias between all five routine assays enable the harmonization of TBA measurements up to 60 μmol/L. However, for patient samples with high TBA levels and disease-specific overrepresentation of individual BAs, harmonization will require: i) optimized reaction conditions to equalize substrate specificity, and ii) calibration to a common, commutable reference material with well-defined BA composition instead of internal standards spiked with different BAs.

Takeda G protein-coupled receptor 5 (TGR5), also known as G protein-coupled bile acid receptor 1 (GPBAR1), is a cell surface receptor involved in key physiological processes, including glucose homeostasis and energy metabolism. Recent research has focused on the role of TGR5 activation in preventing or treating diabetes while also highlighting its potential impact on the progression of diabetic complications. Functional foods and edible plants have emerged as valuable sources of natural compounds that can activate TGR5, offering potential therapeutic benefits for diabetes management. Despite growing interest, studies on the activation of TGR5 by dietary bioactive compounds remain scattered. This Review aims to provide a comprehensive analysis of how dietary bioactives act as potential agents for TGR5 activation in managing diabetes and its complications. It explores the mechanisms of TGR5 activation through both direct agonistic effects and indirect pathways via modulation of the gut microbiota and bile acid metabolism.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD), ulcerative colitis (UC), and IBD unclassified (IBD-U), is a complex intestinal disorder influenced by genetic, environmental, and microbial factors. Recent evidence highlights the gut microbiota as a pivotal biomarker and modulator in IBD pathogenesis. Dysbiosis, characterized by reduced microbial diversity and altered composition, is a hallmark of IBD. A consistent decrease in anti-inflammatory bacteria, such as Faecalibacterium prausnitzii, and an increase in pro-inflammatory species, including Escherichia coli, have been observed. Metabolomic studies reveal decreased short-chain fatty acids (SCFAs) and secondary bile acids, critical for gut homeostasis, alongside elevated pro-inflammatory metabolites. The gut microbiota interacts with host immune pathways, influencing morphogens, glycosylation, and podoplanin (PDPN) expression. The disruption of glycosylation impairs mucosal barriers, while aberrant PDPN activity exacerbates inflammation. Additionally, microbial alterations contribute to oxidative stress, further destabilizing intestinal barriers. These molecular and cellular disruptions underscore the role of the microbiome in IBD pathophysiology. Emerging therapeutic strategies, including probiotics, prebiotics, and dietary interventions, aim to restore microbial balance and mitigate inflammation. Advanced studies on microbiota-targeted therapies reveal their potential to reduce disease severity and improve patient outcomes. Nevertheless, further research is needed to elucidate the bidirectional interactions between the gut microbiome and host immune responses and to translate these insights into clinical applications. This review consolidates current findings on the gut microbiota's role in IBD, emphasizing its diagnostic and therapeutic implications, and advocates for the continued exploration of microbiome-based interventions to combat this debilitating disease.

Stroke represents a predominant cause of mortality and disability on a global scale, impacting millions annually and exerting a considerable strain on healthcare systems. The incidence of stroke exhibits regional variability, with ischemic stroke accounting for the majority of occurrences. Post-stroke complications, such as cognitive impairment, motor dysfunction, and recurrent stroke, profoundly affect patients' quality of life. Recent advancements have elucidated the microbiota-gut-brain axis (MGBA), underscoring the complex interplay between gut health and brain function. Dysbiosis, characterized by an imbalance in gut microbiota, is significantly linked to an elevated risk of stroke and unfavorable outcomes. The MGBA plays a crucial role in modulating immune function, neurotransmitter levels, and metabolic byproducts, which may intensify neuroinflammation and impair cerebral health. This review elucidates the role of MGBA in stroke pathophysiology and explores potential gut-targeted therapeutic strategies to reduce stroke risk and promote recovery, including probiotics, prebiotics, pharmacological interventions, and dietary modifications. However, the current prevention and treatment strategies based on intestinal flora still face many problems, such as the large difference of individual intestinal flora, the stability of efficacy, and the long-term safety need to be considered. Further research needs to be strengthened to promote its better application in clinical practice.

Previous research has identified bile acids (BAs) as a valuable supplement for animal feed, especially in the poultry industry. However, there is limited research on the use of bile acids as a preventative measure against intestinal inflammation in broilers. This study aims to investigate the impact of dietary BAs on LPS-triggered intestinal inflammation in broilers. 180 Arbor Acres broilers were randomly divided into four group: (1) broilers receiving a standard diet (Con group); (2) broilers from the Con category subjected to LPS challenge (LPS group); (3) broilers on a diet supplemented with BAs compound and exposed to LPS (BA+LPS group); and (4) broilers on a diet enriched with lithocholic acid (LCA) and challenged with LPS (LCA + LPS group).The results showed that the LPS challenge caused a notable rise in liver mass, plasma AST concentrations, and levels of inflammatory cytokines (P < 0.05). BAs compounds or LCA improved intestinal morphological damage, inflammation response and bile acid metabolism (P < 0.05). Furthermore, analysis of 16S rRNA gene sequences revealed that supplementation with BAs compounds or LCA mitigated the reduction in bacterial diversity, while also increasing the abundance of operational taxonomic units (OTUs) associated with Bacteroides and Bifidobacterium. Additionally, the increased abundance of Candidatus_Arthromitus due to BAs compound or LCA supplementation showed a significant negative correlation with the concentrations of intestinal inflammatory cytokines (P < 0.05). These results suggest that the supplementation of BAs compound or LCA has the potential to alleviate intestinal inflammation and regulate gut microbiota in broilers subjected to LPS challenge.

In recent decades, obesity and its associated health issues have risen dramatically. The COVID-19 pandemic has further exacerbated this trend, underscoring the pressing need for new strategies to manage weight. Functional foods designed to modulate lipid digestion and absorption rates and thereby reduce the assimilation of dietary fats have gained increasing attention in food science as a potentially safer alternative to weight-loss medications. This review provides insights into controlled lipid digestion and customized delivery of fats. The first section introduces basic concepts of lipid digestion and absorption in the human gastrointestinal tract. The second section discusses factors regulating lipid digestion and absorption rates, as well as strategies for modulating lipid assimilation from food. The third section focuses on applications of controlled lipid digestion in developing personalized foods designed for specific consumer groups, with particular emphasis on two target populations: overweight individuals and infants.

Short-chain fatty acids (SCFAs), produced through fermentation of dietary fibers by gut bacteria, play a central role in modulating cardiovascular function and heart failure (HF) development. The progression of HF is influenced by intestinal barrier dysfunction and microbial translocation, where SCFAs serve as key mediators in the gut-heart axis. This review examines the complex metabolic interactions between SCFAs and other gut microbiota metabolites in HF, including their relationships with trimethylamine N-oxide (TMAO), aromatic amino acids (AAAs), B vitamins, and bile acids (BAs). We analyze the associations between SCFA production and clinical parameters of HF, such as left ventricular ejection fraction (LVEF), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and glomerular filtration rate (GFR). Gaining insights into metabolic networks offers new potential therapeutic targets and prognostic markers for managing heart failure, although their clinical significance needs further exploration.

To evaluate the influence of late cholecystectomy following bariatric surgery on the postoperative evolution of weight loss and biochemical, metabolic, and micronutrient parameters.

A retrospective study that assessed 86 patients who underwent cholecystectomy after at least 18 months of bariatric surgery. The analyzed variables included demographic data, comorbidities, weight loss, and biochemical, metabolic, and micronutrient parameters.

Among the analyzed patients, 20 underwent gastric bypass (GB) and 66 underwent sleeve gastrectomy (SG). The GB group comprised 55% of women, with a mean age of 54.4 years and a mean preoperative body mass index (BMI) of 29.2 kg/m 2 . The mean time elapsed between GB and cholecystectomy was 118.3±43.9 months. The sample of SG comprised 83.3% of women, with a mean age of 41.1 years and a mean preoperative BMI of 28.7 kg/m 2 . The mean time elapsed between SG and cholecystectomy was 26.1±17.5 months. Both SG and GB groups showed a reduction in the mean BMI, but it was not statistically significant after cholecystectomy. In the metabolic, biochemical, and micronutrient evaluation, there was no statistically significant difference, except in the GB group, where an increase in vitamin D was observed after cholecystectomy with statistical significance.

Cholecystectomy does not negatively impact the clinical and anthropometric evolution of patients previously submitted to bariatric surgery.

Bile acid diarrhea is a common but underdiagnosed condition. Because the gold standard test (75SeHCAT) is time-consuming and not widely available, fecal bile acid excretion is typically assessed by chromatography and mass spectrometry. Although enzymatic cycling assays are well established for the rapid and cost-effective analysis of total bile acids (TBA) in serum or plasma, their full potential has yet not been extended to stool samples in clinical routine.

The performance of the 'Total bile acids 21 FS' reagent (DiaSys) was evaluated in fecal matrix according to CLSI guidelines and EU-IVD Regulations (2017/745), and compared to an established microplate-based kit (IDK®) by measuring patient stool samples (n=122). Method agreement was assessed by Passing-Bablok and Bland-Altman analysis. The quantification of eight individual BAs was assessed using HPLC-MS/MS as reference method.

The DiaSys assay showed linearity between 3.5 and 130 μmol/L, good repeatability, total precision, and reproducibility with CVs of 1.7 %, 3.5 %, and 3.0 %. Limit of blank (LoB), detection (LoD), and quantitation (LoQ) were ≤0.17, ≤0.3, and 3.5 μmol/L, respectively. No significant interference from endogenous substances was observed. The methods showed good correlation up to 140 μmol/L (r=0.988), despite differences in the quantification of individual BAs, with mean deviations of 7 % (DiaSys) and 31 % (IDK®), respectively.

The advantages of enzymatic TBA analysis on fully automated clinical chemistry platforms can be exploited for the routine analysis of stool samples. However, cycling assays may benefit from reference standards that take into account the composition of the fecal BA pool.

This study aimed to examine the impact of varying concentrations of bile acids (BA) added to the feed on several aspects of Penaeus vannamei. The purity of BA was 25.29%, and its main components were 5.74% chenodeoxycholic acid, 6.27% allocholic acid, 3.20% cholic acid, 5.79% hyodeoxycholic acid, and 2.31% hyocholic acid. The experiment was designed with four groups: CT, BA1, BA2, and BA3, where BA were added to the shrimp basal diet at concentrations of 0.0 mg/kg, 0.1 mg/kg, 1.0 mg/kg, and 10.0 mg/kg, respectively. After 60 days of farming P. vannamei (initial body weight: 1.21 ± 0.05 g), the results showed that BA supplementation significantly improved growth performance, and BA2 group was the most significant, which increased the final weight (FBW) by 18.6%, weight gain rate (WGR) by 19.5%, and survival rate (SR) by 5.8% compared with the CT group (p < 0.05). Additionally, the activities of trypsin and lipase in gut tissue were significantly increased (p < 0.05). Furthermore, BA supplementation increased the activity of antioxidant-related enzymes in the hepatopancreas and enhanced the mRNA expression levels of gut-associated immune genes. In addition, the supplementation of 0.1 mg/kg BA significantly altered the gut microbial composition, reducing the proportion of harmful Proteobacteria while enhancing the relative abundance of beneficial microorganisms such as Firmicutes and Bacteroides. In conclusion, 1.0 mg/kg and 10.0 mg/kg BA supplementation significantly improved the growth performance, digestive capacity, and antioxidant capacity of shrimp, among which 1.0 mg/kg supplementation had the most significant effect and improved the intestinal microbial composition of shrimp.

As a large and structurally diverse family of small molecules, bile acids play a crucial role in regulating lipid, glucose, and energy metabolism. In the human body, bile acids share a similar chemical structure with many isomers, exhibit little difference in polarity, and possess various physiological activities. The types and contents of bile acids present in different diseases vary significantly. Therefore, comprehensive and accurate detection of the content of various types of bile acids in different biological samples can not only provide new insights into the pathogenesis of diseases but also facilitate the exploration of novel strategies for disease diagnosis, treatment, and prognosis. The detection of disease-induced changes in bile acid profiles has emerged as a prominent research focus in recent years. Concurrently, targeted metabolomics methods utilizing high-performance liquid chromatography-mass spectrometry (HPLC-MS) have progressively established themselves as the predominant technology for the separation and detection of bile acids. Bile acid profiles will increasingly play an important role in diagnosis and guidance in the future as the relationship between disease and changes in bile acid profiles becomes clearer. This highlights the growing diagnostic value of bile acid profiles and their potential to guide clinical decision-making. This review aims to explore the significance of bile acid profiles in clinical diagnosis from four perspectives: the synthesis and metabolism of bile acids, techniques for detecting bile acid profiles, changes in bile acid profiles associated with diseases, and the challenges and future prospects of applying bile acid profiles in clinical settings.

Our previous study demonstrated that γ-cyclodextrin (γ-CD)-perilla oil inclusion complexes increase plasma α-linolenic acid and eicosapentaenoic acid levels in healthy rats without adverse effects. The present study examined the effects of perilla oil, γ-CD, and their inclusion complexes on rats fed cholic acid (CA) to mimic the elevated gastrointestinal 12-hydroxylated (12OH) bile acid levels in high-fat diet-fed rats. Rats fed CA (CA group) tended to have higher AST, ALT, plasma total cholesterol (T-CHO), and triglyceride (TG) levels compared to controls fed a standard diet without CA. Rats fed CA and perilla oil (CA+LP group) showed a tendency for lower AST and plasma TG levels than those in the CA group. Rats fed CA and γ-CD (CA+CD group) had significantly higher AST, ALT, plasma T-CHO, and TG levels than the controls, indicating severe liver injury and dyslipidemia. Rats fed CA and the γ-CD-perilla oil inclusion complex (CA+IC group) had significantly lower AST and ALT levels than the CA+CD rats, with a trend towards lower plasma T-CHO and TG levels. Plasma α-linolenic acid and eicosapentaenoic acid levels were significantly higher in the CA+LP and CA+IC groups than in the controls and CA+CD groups. However, the CA+IC group tended to have lower α-linolenic acid levels and significantly lower eicosapentaenoic acid levels than the CA+LP group. This suggests an accelerated conversion of α-linolenic acid to eicosapentaenoic acid in the CA+IC group, which may contribute to the attenuation of liver injury and dyslipidemia. These findings suggest that γ-CD may exacerbate liver injury and dyslipidemia caused by elevated gastrointestinal 12OH bile acid levels, whereas γ-CD-perilla oil inclusion complexes may ameliorate these effects by altering fatty acid metabolism. Furthermore, we recommend evaluating γ-CD safety in both healthy and pathological models and carefully selecting compounds co-ingested with γ-CD.

Hibernation is a necessary means for animals to maintain survival while coping with low temperatures and food shortages. While most studies have largely focused on mammalian hibernation, its reptilian equivalent has been less studied. In order to provide insights into the energy metabolism and potential microbial regulatory mechanisms in hibernating snakes, the serum, liver, gut content samples were measured by multi-omic methods. Here we show the active snakes have more vigorous lipid metabolism, whereas snakes in hibernation groups have higher sphingolipid metabolism. Furthermore, the results indicate that the potential energy supply pathway was gluconeogenesis. Microbial analysis reveals that Proteobacteria and Firmicutes showed dynamic changes with the transformation among active, pre-hibernation and hibernation periods. The correlation analysis reveals the potential role of Romboutsia, Providencia and Vagococcus in regulating above metabolism by producing certain metabolites. The results advance the understanding of the complex energy-saving strategy in hibernating poikilotherms.

The gut microbiota influences aspects of metabolic disease, including tissue inflammation, adiposity, blood glucose, insulin, and endocrine control of metabolism. Prebiotics or probiotics are often sought to combat metabolic disease. However, prebiotics lack specificity and can have deleterious bacterial community effects. Probiotics require live bacteria to find a colonization niche sufficient to influence host immunity or metabolism. Postbiotics encompass bacterial-derived components and molecules, which are well-positioned to alter host immunometabolism without relying on colonization efficiency or causing widespread effects on the existing microbiota. Here, we summarize the potential for beneficial and detrimental effects of specific postbiotics related to metabolic disease and the underlying mechanisms of action. Bacterial cell wall components, such as lipopolysaccharides, muropeptides, lipoteichoic acids and flagellin, have context-dependent effects on host metabolism by engaging specific immune responses. Specific types of postbiotics within broad classes of compounds, such as lipopolysaccharides and muropeptides, can have opposing effects on endocrine control of host metabolism, where certain postbiotics are insulin sensitizers and others promote insulin resistance. Bacterial metabolites, such as short-chain fatty acids, bile acids, lactate, glycerol, succinate, ethanolamine, and ethanol, can be substrates for host metabolism. Postbiotics can fuel host metabolic pathways directly or influence endocrine control of metabolism through immunomodulation or mimicking host-derived hormones. The interaction of postbiotics in the host-microbe relationship should be considered during metabolic inflammation and metabolic disease.

Xueshuantong injection (Lyophilized) (XSTI) is widely used to treat cardiovascular and cerebrovascular diseases. However, anaphylactoid reactions (ARs) are frequently reported as one of its side effects, and the mechanisms of ARs and their relationship with the different immune status are still not well understood.

This article aims to examine the sensitizing effect of XSTI, explore the impact of normal and immunocompromised states on ARs, and analyze AR-related metabolic pathways by metabolomics.

An immunocompromised mouse model was established through intraperitoneal injection of cyclophosphamide (CTX). Normal and immunocompromised mice were then treated with normal saline (NS), histamine (HIS), and XSTI, respectively. Behavioral responses, auricle blue staining, and Evans blue (EB) exudation were used as indices to evaluate the sensitization of XSTI on both normal and immunocompromised mice. Subsequently, ARs models with different immune statuses were established, and validated by measuring four serum indicators using enzyme-linked immunosorbent assay (ELISA). Finally, LC-MS metabolomics analysis was performed on mouse serum to evaluate the metabolic pathways.

The intensity of ARs induced by XSTI in mice was found to increase with the administered dose, with normal mice exhibiting higher AR intensities compared to immunocompromised mice. Metabolomic analysis revealed significant metabolic changes in XSTI-treated mice. The metabolic pathways predicted from these different metabolites include biotin metabolism, histidine metabolism, glycerolipid metabolism, bile secretion, arachidonic acid metabolism, sphingolipid metabolism, niacin and nicotinamide metabolism, tryptophan metabolism, steroid biosynthesis, and arginine and proline metabolism.

Research indicated that the sensitization of XSTI is dose-dependent, and mice with weakened immune functions exhibit lower sensitivity. Through metabolomics research, the differential metabolites in mice were analyzed, and the metabolic pathways inducing ARs were predicted. This study offers guidance on safe medication from the perspective of organism susceptibility and lays a foundation for research on the potential mechanisms of ARs.

Obesity is one of the major global health concerns of the 21st century, associated with many comorbidities such as type 2 diabetes mellitus (T2DM), metabolic dysfunction-associated steatotic liver disease, and early and aggressive atherosclerotic cardiovascular disease, which is the leading cause of death worldwide. Bile acids (BAs) and incretins are gut hormones involved in digestion and absorption of fatty acids, and insulin secretion, respectively. In recent years BAs and incretins are increasingly recognized as key signaling molecules, which target multiple tissues and organs, beyond the gastro-intestinal system. Moreover, incretin-based therapy has revolutionized the treatment of T2DM and obesity. This mini review highlights the current knowledge about dysregulations in BA homeostasis in obesity with a special focus on atherosclerosis as well as athero-modulating roles of incretins and currently available incretin-based therapies.

The gut microbiota plays a crucial role in maintaining homeostasis and promoting health. A growing number of studies have indicated that gut microbiota can affect cancer development, prognosis, and treatment through their metabolites. By remodeling the tumor microenvironment and regulating tumor immunity, gut microbial metabolites significantly influence the efficacy of anticancer therapies, including chemo-, radio-, and immunotherapy. Several novel therapies that target gut microbial metabolites have shown great promise in cancer models. In this review, we summarize the current research status of gut microbial metabolites in cancer, aiming to provide new directions for future tumor therapy.

Coronavirus disease 2019 (COVID-19) is a global pandemic with high mortality, and the treatment options for the severe patients remain limited. Previous studies reported the altered gut microbiota in severe COVID-19. But there are no comprehensive data on the role of microbial metabolites in COVID-19 patients.

We identified 153 serum microbial metabolites and assessed the changes in 72 COVID-19 patients upon admission and one-month after their discharge, comparing these changes to those in 133 healthy control individuals from the outpatient department during the same period.

Our study revealed that microbial metabolites varied across different stages and severity of COVID-19 patients. These altered microbial metabolites included tryptophan, bile acids, fatty acids, amino acids, vitamins and those containing benzene. A total of 13 distinct microbial metabolites were identified in COVID-19 patients compared to healthy controls. Notably, correlations were found among these disrupted metabolites and organ injury and inflammatory responses related to COVID-19. Furthermore, these metabolites did not restore to the normal levels one month after discharge. Importantly, two microbial metabolites were the core microbial metabolites related to the severity of COVID-19 patients.

The microbial metabolites were altered in the acute and recovery stage, correlating with disease severity of COVID-19. These results indicated the important role of gut microbiota in the progression of COVID-19, and facilitated the potential therapeutic microbial target for severe COVID-19 patients.

HY209 is a synthesized sodium taurodeoxycholate (TDCA) that is expected to serve as a novel treatment for sepsis by inhibiting the inflammasomal activation that suppresses the production of pro-inflammatory cytokines. This study aimed to assess the safety, tolerability and pharmacokinetics (PKs) of HY209 after intravenous administration in healthy subjects.

A dose-block randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Eight subjects in each dose group were randomized to receive an intravenous administration of HY209 (0.1, 0.2, 0.4, 0.8 and 1.6 mg/kg) or a placebo at a 3:1 ratio. Safety and tolerability variables including adverse events (AEs) and vital signs were monitored. For the PK analysis, serial blood samples were collected for 72 hours at baseline and up to 24 hours post-dose. A power model was used to evaluate the dose-proportionality of HY209. Given that TDCA is an endogenous compound, time-matched baseline differences in plasma concentrations were analyzed.

A total of 39 subjects completed the study. All AEs were mild, and no serious AEs were observed. There was no significant correlation between the frequency of AEs and the administered dose. A circadian pattern was observed in the plasma TDCA concentration at baseline. After infusion, the plasma TDCA was rapidly eliminated; the plasma TDCA concentration at one hour after the end of infusion showed no significant differences from the baseline. The baseline-adjusted maximum plasma concentration of TDCA demonstrated dose-proportionality in a HY209 range of 0.1-1.6 mg/kg.

A single intravenous administration of HY209 was well tolerated and its systemic exposure showed dose-proportionality in a dose range between 0.1 and 1.6 mg/kg.

Edible fungi polysaccharides (EFPs) and gut microbiota (GM) play an important role in lipid metabolism. The structure of GM is complex and can be dynamically affected by the diet. EFPs can be used as dietary intervention to improve lipid metabolism directly, or by regulate the GM to participate in the host lipid metabolism by a complex mechanism. In this paper, we reviewed that EFPs regulate the balance of GM by increasing the number of beneficial bacteria and decreasing the number of harmful bacteria in the intestinal tract. The metabolites of GM are mainly bile acids (BAs), short-chain fatty acids (SCFAs), and lipopolysaccharides (LPS). EFPs can promote the synthesis of BAs and increase the content of SCFAs that produced by GM fermented EFPs, but reduce the content of LPS to regulate lipid metabolism. This review provides a valuable reference for further elucidation of the relationship between EFPs-GM-lipid metabolism and EFPs targeted regulation of GM to improve public health.